Plasmodium falciparum is the most common parasite to infect central nervous system and the leading cause of diffuse encephalopathy in young children. This encephalopathy is associated with 10-14% of mortality with an estimated annual death of 1-2.5 million annual deaths. P. falciparum is the most lethal species among the four human malaria parasites (P. falciparum, P. vivax, P. malariae, P. ovae) and it has been estimated that it infects 300-500 million people per year. About 1% of all cases of falciparum malaria results in cerebral malaria and thus affects central nervous system at least in 3 million people especially young children. In the absence of effective vaccine to protect against malaria coupled with the increasing anti-malaria drug resistance globally, malaria is re-emerging as a major public health threat in the tropics and subtropics. Most of the studies conducted to date to understand the long and short term effects of malaria on brain and brain function have focused largely on malaria-induced gross neurological defects but very little data is available on the impact of this disease on learning cognitive function and neuro-psychology. Previous studies in our laboratory using human post mortem brain and serum samples from West Africa indicated that RANTES and corresponding receptors CCR1, CCR3, and CCR5, play a very important role in brain immunopathogenesis that may result in neurological impairment or dysfunction. We hypothesize that cerebral malaria induces neurological impairment and reduces cognitive function. A corollary to this hypothesis is that this neurological impairment is mediated by immunopathogenesis. We propose a multidisciplinary international partnership involving Morehouse School of Medicine, Centers of Disease Control and the Medical Research Center (ICMR), Jabalpur, India to address the role of immunopathogenesis in malaria-induced neurological impairment following P. falciparum malaria in a population most affected by malaria in the sub-continent of India. The first specific aim will conduct preliminary retrospective and prospective epidemiological investigations to assess the extent of long-term neurological impairment associated with CM caused by P. falciparum in central India where falciparum malaria i s widespread. The second specific aim will conduct preliminary investigations to determine the potential immunopathological factors associated with neurological impairment after recovery from cerebral malaria. This proposal will pursue epidemiology and molecular immunology of cerebral malaria as well as capacity building in India. Data from the proposed research will reveal t he molecular basis of cerebral malaria induced neurological and cognitive impairment.